Micromechanic passive flow regulator

ABSTRACT

The invention concerns a flow regulator, made of a stack of 3 plates, respectively a top plate including a flexible membrane ( 1 ), a middle plate ( 2 ) with pillars and through holes and a bottom plate ( 3 ) with fluidic ports, micro channels and through holes ( 8,9,12 ). The principle is based on the deformation of the membrane due to the pressure of the liquid. The membrane goes in contact with the pillars of the middle plate, obstructing gradually the through holes of the pillars. The device is designed to keep the flow constant in a predefined range of pressure. The device is dedicated to ultra low flow rate up to 1 ml per day or below, typically for drug infusion. Plastic flow regulators comprise preferably several independent valves coupled in parallel. The membrane plate is therefore made of several flexible membranes obstructing gradually the flow by increasing the pressure. Stress limiters are used to avoid plastic deformation of the membrane. For implanted pump, the use of a flow regulator instead of a flow restrictor has several advantages, including the possibility to reduce significantly the reservoir pressure and to generate directly the pressure during the pump filling by using an elastic drug reservoir.

FIELD OF THE INVENTION

The present invention relates to fluid flow regulators used in the fieldof drug delivery, the drug being either liquid or gaseous, for instancefor pain management. Such flow regulators can also be used for drainingcerebrospinal fluid (CSF) for hydrocephalus patient. The inventionfurther relates to fabrication processes of such flow regulators.

STATE OF THE ART

Passive drug infusion devices, in contrast to active ones, do not relyon a pump to deliver a drug but rather on a pressurized drug reservoir.A known problem of these passive devices is that the drug flow rate to adelivery location, which may be a patient's body for instance, may varyas a function of the amount of drug remaining in the reservoir as far asthe pressure in the reservoir depends on this amount. Such passivedevices are thus usually provided with a fluid flow regulator to ensurethat the drug flow rate is as constant as possible with respect to theamount of drug remaining in the reservoir.

An example of such a passive drug flow regulator is available by theApplicant under the registered name “Chronoflow” and is disclosed inU.S. Pat. No. 6,203,523 B1. This device comprises a fluid inlet adaptedto be connected to a fluid reservoir and a fluid outlet adapted to beconnected to a patient's body. It comprises a rigid substrate and aresilient membrane tightly linked together in peripheral linking areasso as to define a cavity therebetween. This cavity is connected to thefluid outlet while the membrane has a first surface opposite the cavitywhich is connected to the fluid inlet. The membrane has a centralthrough hole contiguous with the cavity, to define a pathway for a fluidfrom the fluid inlet to the fluid outlet, and is flexible so as to beable to come into contact with the substrate, in case a fluid wouldapply a pressure on the first surface that would be larger than a firstpredefined threshold value. As the membrane would come into contact withthe substrate in the region of its central through hole, this wouldocclude the latter and result in hindering a fluid from flowing throughit.

This device further comprises a flow regulator open channel etched inthe substrate with an inlet facing the central through hole of themembrane and an outlet connected to the outlet of the device. Thischannel is in the shape of a spiral curve such that, the more pressureis applied against the membrane, the more it closes the channel thusforcing the fluid to flow in it to find its way out of the cavity.

Consequently, when the pressure applied on the membrane increases, thelength of the fluid pathway located within the flow regulator channelincreases and so does the fluidic resistance of the device. Thus, theflow rate may be kept approximately constant within a predefined rangein terms of the reservoir pressure.

However, fabrication of such a device is complicated and expensive.Indeed, the substrate has to be etched according to a specific pattern,which is rather delicate regarding the accuracy level that has to berespected for the flow regulation to operate properly. Thus, not onlythe manufacture of the substrate requires specific extra-steps, but alsothese steps are further delicate to carry out. Depending on thedimensions of the device, specific materials such as SOI is to be usedfor manufacture of the substrate, which is still more expensive. It isalso important to note that this device is sensitive to particles. Thelarge contact area between the membrane and the substrate at highpressure can be problematic since any particle in this area will inducea leakage.

Moreover, the device manufactured through this process is then designedfor one specific set of parameters regarding delivery of a drug, i.e.predefined reservoir pressure range and average flow rate. Complexfluidic simulations of such device are necessary to estimate the spiralshape and to take into account the flow restriction outside of thechannel, making any design change difficult.

Park reports another constant flow-rate microvalve for hydrocephalustreatment [S. Park, W. H. Ko, and J. M. Prahl, “A constant flow-ratemicrovalve actuator based on silicon and micromachining technology,” inTech. Dig. 1988 Solid-State Sens. Actuator Workshop (Hilton Head '88),Hilton Head Island, S.C., Jun. 6-9 (1988) 136-139]. The valve is alsomade of a diaphragm covering a flat substrate; the channel cross-sectiondiminishes under increasing pressure, thus leading to quasi-steadyflow-rate. Both theoretical and experimental data reported show that aperfectly steady rate cannot be achieved since the flow resistanceshould increase with the applied pressure in a linear manner and thechange of the cross-section of the channel is strongly non-linear. Thisnon-linearity is not compensated by the use of a spiral channel. Alllimitations discussed for the design described in U.S. Pat. No.6,203,523 B1 are present here.

Kartalov reports a PDMS-based device for passive flow regulation ofNewtonian fluid [E. P. Kartalov, C. Walker, C. R. Taylor, W. F.Anderson, and A. Scherer, “Microfluidic vias enable nested bioarrays andautoregulatory devices in Newtonian fluids,” Proc. Nat. Acad. Sci. 103(2006) 12280-12284]. This device is made of a three-dimensionalstructure showing an important dead volume. The autoregulated devicecomprises a main channel between a source and an exhaust, the staticpressure decreases as the fluid flows along this channel which alsocomprises a flexible membrane called pushup valve. The static pressureremains constant along the dead-end detour channel leading to the valve.The pushup valve experiences an effective pressure equal to the staticpressure drop between the channel split and the main channel segmentabove the valve. As the pressure drop increases, the valve membranedeforms upward and constricts the main channel, leading to an increaseof the fluidic resistance with applied pressure and thus to nonlinearityfor Newtonian fluids. The presence of dead-ends for such devices makesthe priming difficult. Air trapped below the valve would induce dampingeffect. But the main drawback of such devices is the flow-rate accuracy.The use of plastic parts is very attractive in terms of cost but itseems very difficult to achieve a controlled deflection of the valve inorder to get a constant flow rate. For high modulus plastic, themembrane will experience non-linear and thus plastic deformation duringoverpressure, leading to irreversible damages. In any case, the changeof the cross-section of the channel is strongly non-linear and thedevice cannot achieve, by design, a constant flow-rate. Moreover, andaccording to the Poiseuille' s law, it is difficult to match thefabrication tolerances of plastic microchannels and membranes to theflow rate accuracy expected for medical infusion of drugs.

Microfluidic autoregulation using the non-Newtonian rheologicalproperties of concentrated polymeric solutions have been reported byGroisman [Groisman et al., (2003) Science 300, 955-958]. For medicalapplication, one of the main limitations of such device is the use ofbiocompatible polymer solution.

A passive flow regulator that exploits the large compliance ofelastomeric polymers has been proposed by Yang [B. Yang and Q. Lin, APlanar Compliance-Based Self-Adaptive Microfluid Variable Resistor,Journal of microelectromechanical systems 16 (2007) 411-419]. The devicecomprises a thin flap and a stiff stopper. The gap between the flap andthe stopper varies with the applied pressure, resulting in a non-linearresistance. Constant flow-rates of 0.21 ml/min and 1.2 ml/min between100 and 200 kPa have been obtained for two different devices using DIwater. Here again, we do not expect high reproducibility and accuracyfrom one device to another because of the plastic fabricationtolerances. This limitation is particularly problematic at lowflow-rate, typically below 1 ml per hour.

Saaski et al. disclose in U.S. Pat. No. 5,839,467 a device having amembrane tightly attached to a substrate that have a cavity and acentral pillar having a through hole. The inlet is located on thelateral side of the substrate. The fluid flows from this inlet towardsthe outlet located after the through hole of the substrate pillar. Themembrane side opposite to the pillar is submitted to the reservoirpressure. The small gap between the upper part of the pillar and themembrane forms a large fluidic restriction. By increasing the reservoirpressure the membrane deflects towards the pillar, reducing the gapheight between the pillar and the membrane. The device can be consideredas a valve which can shut off when the reservoir pressure increases,i.e. when the gap height between the pillar and the membrane becomesequal to zero. In that case, the pressures on both sides of the membraneare equal excepted above the pillar area. Various configurationsincluding check-valve feature, shut-off feature, device having amembrane with a through hole and a non-drilled pillar are disclosed. Foreach proposal, the flow rate can be therefore more or less controlled upto the closing of the valve but in any case a constant flow rate can beachieved because of the non-linearity of the fluidic resistance of thatvalve as the gap height varies. Moreover, the fact that the reservoirpressure applies directly on both sides of the membrane makes necessarythe use of a small gap between the pillar and the membrane at anypressure otherwise the device do not regulate the flow. The gap 48disclosed of only 2.5 microns (FIG. 6) is an illustration of thisfeature. The device is therefore very sensitive to particles. Relativemachining tolerances for this gap are also difficult to achieve.

Patent application WO2008/094672A2 discloses capacitive type fluidicvalves made of several layers and comprising lateral ports, a flexiblemembrane and a substrate having a pillar with a hole. By changing thefluid pressure the membrane deflects towards the pillar and increasesthe fluidic resistance of the valve. Only one side of the membrane is incontact with the fluid. The fluid can flow up to the valve via channelsdirectly machined or formed in the substrate plate. These channels shallnot exhibit a fluidic resistance of the same order of magnitude of thatof the valve itself otherwise the damping effect due to the membranedeflection is no longer efficient. The non-linearity of the membranedeflection with the fluid pressure prevents the possibility to reach aconstant flow rate or a flow rate having a specific profile over a givenrange of pressure.

Patent application DE4223067A1 discloses a device having lateral fluidicports, one flexible membrane that comprises one pillar having onethrough hole. The functioning principle is very similar to the previousexample of flow regulators and therefore the device shows the samelimitations in term of accuracy.

Patent application FR2905429 discloses a device having resilientpolymeric membrane as a part of a reservoir and also as part of a valveor two separated resilient membranes for the reservoir and the valve, asubstrate having a hole and a pumping mechanism. The resilient membranesshow no opening. The valve disclosed in the document has an anti-freeflow function and therefore the membrane should comply with the valveseat to ensure tightness. This compliance is not compatible with thepossibility to regulate the flow according to a specific profile becauserigid membrane is necessary.

To summarize the state-of-the-art, we can point out that all devices arenot adapted to flow rate lower than 1 ml per hour because thefabrication tolerances and the designs themselves strongly limit theflow rate accuracy, making the device not suitable for medical use.

Passive regulators disclosed in the U.S. Pat. No. 6,203,523 B1 and WO2,009,098,314 A1 are preferably made in silicon. The designs are basedon a non-linear deformation of an elastic membrane and therefore siliconis used as membrane thanks to its high yield strength and low internalstress.

A new design adapted to the use of other materials like plastics for themembrane is desirable.

Passive flow regulators may advantageously be used in hydrocephalustreatment. Hydrocephalus is usually due to blockage of CSF outflow inthe ventricles or in the subarachnoid space over the brain.Hydrocephalus treatment is surgical: it involves the placement of aventricular catheter (a tube made of silastic for example) into thecerebral ventricles to bypass the flow obstruction malfunctioningarachnoidal granulations and the draining of the excess fluid into otherbody cavities, from where said fluid can be resorbed. Most of the CSFshunts have been based on the principle of maintaining a constantintracranial pressure (ICP) regardless of the flow-rate of CSF. The CSFshunts have been constructed to cut off CSF-flow when the differentialpressure between the inlet and the outlet of the CSF shunt was reducedto a predestined level, called the opening pressure of the shunt. Anexample of an ICP shunt is shown in U.S. Pat. No. 3,288,142 to Hakim,which is a surgical drain valve device used to control the drainage offluid between different portions of the body of a patient, particularlyfor draining cerebrospinal fluid from the cerebral ventricles into theblood stream (co called ventriculo-atriostomy).

Clinical experience has proven that this principle of shunting is not anideal solution. Sudden rises of the ICP, e.g. due to change of position,physical exercise, or pathological pressure waves result in excessiveCSF drainage. Several reports in the literature (Aschoff et al., 1995)point at problems due to this overdrainage, and especially thepronounced narrowing of the ventricles has been pointed out as being themain factor leading to malfunctioning of the implanted shunting device.The reason is that the ventricular walls may collapse around theventricular CSF shunt device, and particles (cells, debris) may intrudeinto the shunt device. U.S. Pat. No. 5,192,265 to Drake et al. describesan example of a shunt seeking to overcome the above-mentioneddifficulties by proposing a rather complex anti-siphoning deviceallowing to select transcutaneously the resistance to flow bycontrolling the pressure in a chamber gas-filled and being in pressurecommunication with one flexible wall of the main chamber where the flowis regulated.

The use of programmable valves was associated with a reduction in therisk of proximal obstruction and overall shunt revision, one possibleexplanation for a difference in the two populations studied is thatprogrammable valves may allow the physician to avoid such ventricularcollapse by increasing the valve pressure setting after noting clinicalsigns and symptoms and/or radiological evidence of overdrainage. In thisway, proximal obstruction is prevented, and shunt revision surgery isavoided. One such adjustable valve is described in U.S. Pat. No.4,551,128 to Hakim et al. However, due to the elastomeric properties ofthe diaphragm material, maintenance of the implanted valve may berequired. Further, flow rate adjustment of this adjustable valve afterimplantation may require a surgical procedure. Another adjustable valvemechanism, described in U.S. Pat. No. 4,781,673 to Watanabe, includestwo parallel fluid flow passages, with each passage including a flowrate regulator and an on-off valve. Fluid flow through the passages ismanually controlled by palpably actuating the on-off valves through thescalp. Although the Watanabe device permits flow rate control palpablythrough the scalp and thus, without surgical intervention, patientand/or physician attention to the valve settings is required.

One system, described in U.S. Pat. No. 6,126,628 to Nissels, describes adual pathway anti-siphon and flow-control device in which both pathwaysfunction in concert. During normal flow, both the primary and secondarypathways are open. When excessive flow is detected, the primary pathwaycloses and flow is diverted to the high resistance secondary pathway.The secondary pathway decreases the flow rate by 90% while maintaining adrainage rate within physiological ranges, which prevents the damagingcomplications due to overdrainage. However, this device is intended foruse with a shunt system including a valve for controlling flow rate andshould be placed distal to the valve inducing cumbersome procedure dueto the additional material to be implanted. The system can be used as astand-alone only for low-pressure flow-control valve.

Another application of passive flow regulators is the infusion of drugs.Current implantable pumps for pain management deliver few millilitersper day (Codman®3000, IsoMed®). The system can be pressurized by a gaslike a lighter. The gas pushes the drug into a capillary and the flowrate is directly proportional to the difference between the vapourpressure of the gas and the atmospheric pressure. In order to beindependent from any change of the atmospheric pressure, the vapourpressure of the gas is typically larger than 2 bars, making the refillprocedure rather difficult.

It is therefore desirable to have an easy-to-use and efficient flowregulator dedicated to ultra low flow rate, typically 4 ml per day orbelow.

Replacing the flow restrictor of current implantable pumps by a flowregulator would allow a significant lowering of the vapour pressure ofthe gas up to a factor ten or more. This feature would facilitate thepump filling. It is also possible to use a larger set of pressurizationsystems, including of course the gas propeller system, an elastomericreservoir that pushes the liquid through the flow regulator, a softreservoir and a spring that is compressed during the filling of the pump. . . . Finally, the use of a flow regulator would significantly reducethe risk of overdose due to a shock.

General Description of the Invention

The aim of the present invention to propose a passive fluid flowregulator that overcomes the above-mentioned drawbacks. Another aim ofthe present invention is to offset the drawback of the prior artmentioned above by proposing, as an alternative, a passive fluid flowregulator which is easier and cheaper to manufacture and which wouldprovide more flexibility and accuracy as far as its conditions of useare concerned.

To that end, the present invention relates to a flow regulatorcomprising a fluid inlet adapted to be connected to a fluid reservoirand a fluid outlet adapted to be connected to a delivery location, saidregulator comprising a rigid substrate and a flexible membrane tightlylinked together in predefined linking areas, said substrate and/or saidmembrane having a recess so as to define—when said membrane is in a restposition—a cavity between said membrane and said substrate; saidsubstrate and/or said membrane having a through hole contiguous withsaid cavity and communicating with said fluid outlet, said substrateand/or said membrane furthermore comprising two additional through holescontiguous with said cavity and communicating with said fluid inlet;said substrate and/or said membrane having at least two pillars withinsaid cavity, the height of each of said pillars being such that, whensaid membrane is at rest, a gap is formed between the pillar free endand the opposite cavity wall; each of said pillars being furthermorealigned with one of said additional through holes and forming a valve insaid gap; said pillars furthermore having a width that is larger thanthe width of said aligned through hole; said flexible membrane beingable to come into contact with at least a first part of said substrate,within said cavity and with a portion including a first of said valves,in case a greater pressure than a first predefined threshold value isapplied on the surface of the membrane opposite to the said substrate,which results in lowering said gap height up to zero and hindering afluid from flowing through said first valve, said flexible membranebeing able to come into contact with at least a second part of saidsubstrate, within said cavity and with a portion including a second ofsaid valves, in case a pressure larger than a second predefinedthreshold value is applied on the surface of the membrane opposite tothe said substrate, which results in hindering a fluid from flowingthrough said second valve, wherein the pillars and the additionalthrough holes positions and dimensions are arranged so that the fluidflow rate is passively regulated at least in a range of inlet pressuregoing from said first and said second predefined threshold values.

Preferred embodiments of the inventions are defined in the dependentclaims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will be better understood at the light of thefollowing detailed description which contains non-limiting examplesillustrated by the following figures:

FIG. 1 a shows a simplified cross-sectional view of a fluid flowregulator according to the first preferred embodiment of the presentinvention, wherein the through holes are machined in the pillars.

FIG. 1 b shows a simplified cross-sectional view of a fluid flowregulator according to the second preferred embodiment of the presentinvention, wherein the through holes are machined in the membrane.

FIG. 2 a shows a simplified cross-sectional view of a fluid flowregulator according to another embodiment of the present invention,wherein the membrane is flat and wherein the channels are machined intothe bottom plate.

FIG. 2 b shows a simplified cross-sectional view of a fluid flowregulator according to another embodiment of the present invention,wherein the channels are machined into the pillar plate.

FIG. 2 c shows a simplified cross-sectional view of a fluid flowregulator according to another embodiment of the present invention,wherein the channels are machined into both bottom and pillar plates.

FIG. 3 shows a simplified cross-sectional view of a fluid flow regulatoraccording to another embodiment of the present invention, wherein themembrane is etched to form a recess.

FIG. 4 a shows a first simplified cross-sectional view of a fluid flowregulator according to another embodiment of the present invention,wherein the channels are machined into the SOI layer of the pillar plateand wherein the recess is machined in the membrane.

FIG. 4 b shows a second simplified cross-sectional view of a fluid flowregulator according to another embodiment of the present invention,wherein the channels are machined into the SOI layer of the pillar plateand wherein the recess is machined in the pillar plate.

FIG. 4 c shows a third simplified cross-sectional view of a fluid flowregulator according to another embodiment of the present invention,wherein the channels are machined into the SOI layer of the pillar plateand wherein the recess is machined in both the membrane and the pillarplate.

FIG. 4 d shows a fourth simplified cross-sectional view of a fluid flowregulator according to another embodiment of the present invention,wherein the channels are machined into the SOI layer of the bottom plateand wherein the recess is machined in the membrane plate.

FIG. 5 shows a simplified cross-sectional view of a fluid flow regulatoraccording to another embodiment of the present invention, comprising amembrane plate and a pillar plate, wherein the flow restrictors arelocated either in the through hole of the pillar plate and/or in atubing connected to the through hole of the substrate and/or in adedicated device connected via a tubing to the through hole of thepillar plate.

FIG. 6 a shows a simplified front-view of a valve according to the firstpreferred embodiment of the present invention, comprising ananti-bonding layer on the back-side of the membrane.

FIG. 6 b shows a simplified front-view of a valve according to the firstpreferred embodiment of the present invention, comprising ananti-bonding layer on the front-side of the pillar plate.

FIG. 7 a shows a simplified front-view of a channel machined in eitherthe bottom or the pillar plate.

FIG. 7 b shows a simplified front-view of a pillar plate according toany of the preceding embodiments of the present invention, comprising afirst cavity defining the gap between the pillars and the membrane, anda second cavity defining the height of the pillars.

FIG. 8 a shows a simplified side-view of the another embodiment of thepresent invention, the regulator having membranes and gaps of variousdimensions and undergoing a first low pressure value.

FIG. 8 b shows a simplified side-view of another embodiment of thepresent invention, the regulator having membranes and gaps of variousdimensions and undergoing a second larger pressure value;

FIG. 9 a shows a simplified front-view of the pillar plate according toanother embodiment of the present invention, wherein the pillar cavitiesare squares and the outlet hole is located between the two pillars.

FIG. 9 b shows a simplified example of membrane backside (etched side)according to another embodiment of the present invention, wherein thecavities are squares.

FIG. 10 shows a simplified front-view of a valve according to anotherembodiment of the present invention, comprising both Stress LimiterPillars (SLP) and Stress Limiter Steps (SLS).

FIG. 11 shows an example of a simplified view of a stress limiter pillaraccording to another embodiment of the present embodiment.

FIG. 12 shows an example of a simplified valve cross-section accordingto another embodiment of the present invention, wherein the stresslimiter pillars and the valve pillars are on the membrane backside.

FIG. 13 a shows a simplified valve cross-section according to anotherembodiment of the present invention, wherein the pillar plate comprisesstress limiter steps and valve pillar and wherein the membrane has ahole at its centre.

FIG. 13 b shows a simplified bidirectionnal valve cross-sectionaccording to another embodiment of the present invention, comprising afirst pillar plate, a drilled membrane plate and a second pillar plate.

FIG. 13 c shows a simplified view of a check-valve cross-sectionaccording to another embodiment of the present invention, comprising afirst pillar plate having a pillar in contact with the membrane, amembrane plate having a hole and a second pillar plate.

FIG. 14 a shows a simplified plan view of a bottom plate or pillar platebackside according to a further exemplary embodiment of the presentinvention.

FIG. 14 b shows a simplified plan view of a thin film intended tocooperate with the bottom plate or pillar plate backside of FIG. 14 a.

FIG. 14 c shows a simplified plan view of the bottom plate or pillarplate backside of FIG. 14 a when covered with the thin film of FIG. 14b.

FIG. 15 a shows a simplified plan view of the first embodiment of thepresent invention with additional protective top cap and a fluidicswitch in position 1 wherein the pressure is transmitted from thereservoir to only the inlet of the device.

FIG. 15 b shows a simplified plan view of the first embodiment of thepresent invention with additional protective top cap and a fluidicswitch in position 2 wherein the pressure is transmitted from thereservoir to both device inlet and protective cap cavity.

FIG. 16 shows the simulated flow rate versus pressure characteristic ofa passive flow regulator having a silicon membrane according to thedimensions given in table 1.

FIG. 17 shows the simulated flow rate versus pressure characteristic ofa passive flow regulator having a silicon membrane according to thedimensions given in table 2.

FIG. 18 shows the simulated flow rate versus pressure characteristic ofa passive flow regulator having a PMMA membrane according to thedimensions given in table 3.

In a first preferred embodiment of the invention, the device is made ofa stack of 2 plates:

-   -   A top layer with a flexible membrane 1 (called hereafter        membrane)    -   A middle plate 2 with pillars 4 having through holes 11, cavity        5, inlet ports 9 and outlet port 10 (called hereafter pillar        plate)

A simplified side view of the device is shown in FIG. 1 a (not atscale).

As for all side views of the present invention, the direction of theflow is indicated by gray arrows.

Principle of the Device According to the First Embodiment of the PresentInvention:

The pillar plate 2 is tightly linked to the membrane 1 in predefinedlinking areas 16.

The membrane 1 has two sides: the front side of the membrane 70 (uppersurface) is submitted to the pressure of the fluid reservoir notrepresented in FIG. 1 a whilst the back side of the membrane 71 islocated within a recess 21 in front of the pillar plate. The recess 21of the membrane is connected to a cavity 5 in the pillar plate 2. Thepillar plate 2 contains pillars 4 having through holes 11, said pillarsbeing surrounding by the cavity 5 which is connected to a large outletthrough hole 60 and an outlet port 10. The cavity 5 is thereforesubmitted to the outlet pressure except in front of the pillar. Bydesign, the pillar areas 4 should be at least 10 times smaller that theareas of the cavity 5.

When the membrane is at rest position, i.e. when there is no pressure inthe fluid, the membrane back side 71 in front of the pillar 4 forms avalve 6 having an initial gap 7. The valve 6, made of the annularfluidic restriction between the membrane back-side 71 and the top of thepillar 4, has an inlet (through hole 11) and an outlet (cavity 5).

FIG. 1 a shows a fluidic pathway (gray arrows) that is made of the inletports 9, the through holes 11 in the pillar plate 2, the valve 6, thecavity 5, the outlet through hole 60 and finally the outlet port 10.

The inlet ports 9 are connected to the reservoir at the pressureP_(reservoir) and the outlet through hole 60 and outlet port 10 areconnected to the delivery location at the pressure P_(out).

The pressure reservoir induces a flow according to said fluidic pathway.Because the opening of the valve 6 (equal to the initial gap withoutpressure) depends on the reservoir pressure since by increasing thereservoir pressure, the membrane 1 moves towards the pillars 4 of thepillar plate 2, obstructing gradually the through holes 11 of thepillars 4 and therefore closing gradually the valves 6, the fluidicresistance of the valve depends on the pressure. Except the fluidicresistance of the cavity which depends also on the pressure because itsheight depends on the membrane deflection and therefore on the reservoirpressure, all other parts of the fluidic pathway show constant fluidicresistances.

The operating principle of the device imposes that the fluidicresistance of the inward part of the fluidic pathway (respectivelybetween the inlet port 9 and the valve 6) is at least ten times largerthat the fluidic resistance of the downward part of the fluidic pathway(that comprises the cavity, the outlet through hole 60 and the outletport 10). The obvious corollary is that the fluidic resistance of thecavity, which depends on reservoir pressure, should be at least tentimes smaller that the fluidic resistance of the inward fluidic pathwaywhatever the reservoir pressure.

In a first approximation, the flexible part of the membrane is thereforesubmitted to a gradient of pressure equal to the difference between thereservoir pressure and the outlet pressure.

Any change of the reservoir pressure induces a change of the valveopening and therefore to their fluidic resistances. For such annularvalves, and according to the discussion in the state of the artparagraph, the fluidic resistance of such valves is not linear butvaries as the power of −3 with their opening height. The use of only onevalve is not sufficient to offer the possibility of the constant flowrate or any specific flow profile when the reservoir pressure changes.

To get a constant flow rate over a given range of pressure, it isnecessary to implement at least two valves that are closed gradually butnot at the same rate when increases the reservoir pressure. In practice,the valve located near the centre of the membrane 1 will be closed firstwhile the valves located near the edge of the membrane need higherpressures to shut off. The diameters of the through holes 11, thepositions of the pillars 4, the diameter and thickness of the membrane 1and finally the height of the cavity 21 are chosen to obtain a constantflow rate over a specified range of pressure.

As a general trend, the higher the number of valves the better the flowaccuracy.

In a second preferred embodiment of the invention, the device is made ofa stack of 2 plates:

-   -   A top layer with a flexible membrane 1 having through holes 208

    -   A middle plate 2 with full pillars 4, cavity 5, inlet ports 9        and outlet port 10

    -   

A simplified side view of the device is shown in FIG. 1 b (not atscale).

The fluid of the reservoir is in contact with the upper surface 70 ofthe membrane 1. The pressure in the reservoir induces a flow through thethrough holes 208, the valve 6, the cavity 5 and finally the outletthrough hole 60 and the outlet port 10. The operating principle is verysimilar to the first preferred embodiment of the present invention: anychange of the reservoir pressure modifies the opening of the valves 6and therefore their fluidic resistances. The holes in the membrane havea fluidic resistance at least ten times larger than any other part ofthe fluidic pathway when the membrane is at rest position (no pressurein the reservoir). The device may be designed to ensure that the fluidicresistance remains constant over a specified range of pressure.

To form a valve 6, the full pillars 4 are machined in front of thethough holes 208 of the membrane 1. Depending on the regulation profiledesired, typically if a free flow at large pressure is needed, one orseveral through holes 208 may be located in front a the cavity 5 whereinthere is no pillar. Pillars are not systematically placed in front of ahole, typically when there is a need to have a support for the membraneat high pressure or when the dead volume of the device should beoptimized.

In order to ensure a very low flow rate regulation, typically fewmilliliters per day or less, the through holes 11 in the pillar 4 or thethrough holes 208 in the membrane 1 should have diameters of fewmicrons. Because the relative machining tolerances for such tiny holesis large using MEMS processes or plastic injection, the final accuracyof the device is bad. There is a need to another regulator design forlow flow regulation. The later design will be based on the firstpreferred embodiment of the present invention.

In another embodiment of the invention, the device dedicated to low flowrate is made of a stack of 3 plates:

-   -   A top layer with a flexible membrane 1    -   A middle plate 2 with pillars 4, through holes 11 and eventually        channels 8    -   A bottom substrate 3 with fluidic ports 9 and 10 and eventually        channels 8 (hereafter called bottom substrate)

A simplified side view of the device is shown in FIG. 2 a (not atscale).

Principle of the Device According to this Another Embodiment of thePresent Invention Dedicated to Low Flow Rate:

The pillar plate 2 is tightly linked to the membrane 1 and the bottomplate 3 in predefined linking areas 16 and 17 respectively. The cavity 5between the membrane and the pillar plate has a large outlet throughhole 60 compared to the other through holes in order to ensure that thepressure within the cavity is very close to the outlet pressure.

The membrane 1 has two sides: the front side of the membrane 80 (uppersurface) is submitted to the pressure of the fluid reservoir notrepresented in FIG. 2 a whilst the back side of the membrane 81 (lowersurface in front of the cavity 5 and pillars 4) is submitted to theoutlet pressure except in front of the pillar. By design, the pillarareas 4 should be at least 10 times smaller that the areas of the cavity5.

When the membrane is at rest position, i.e. when there is no pressure inthe fluid, the membrane back side 81 in front of the pillar 7 forms avalve 6 having an initial gap 7. The valve 6, made of the annularfluidic restriction between 81 and 4, has an inlet (through holes 11)and an outlet (cavity 5).

FIG. 2 a shows a fluidic pathway (gray arrows) that is made of the inletports 9, the through holes 12 in the bottom plate, the channels 8between the bottom plate and the pillar plate, the through holes 11 inthe pillar plate, the valve 6, the cavity 5, the outlet through hole 60and finally the outlet port 10.

The inlet ports 9 are connected to the reservoir at the pressureP_(reservoir) and the outlet through hole 60 and outlet port 10 areconnected to the delivery location at the pressure P_(out).

The pressure reservoir induces a flow according to said fluidic pathway.Because the opening of the valve 6 (equal to the initial gap withoutpressure) depends on the reservoir pressure since by increasing thereservoir pressure, the membrane 1 moves towards the pillars 4 of themiddle plate 2, obstructing gradually the through holes 11 of thepillars 4 and therefore closing gradually the valve 6, the fluidicresistance of the valve depends on the pressure. Except the fluidicresistance of the cavity which depends also on the pressure because itsheight depends on the membrane deflection and therefore on the reservoirpressure, all other parts of the fluidic pathway show constant fluidicresistances.

The operating principle of the device imposes that the fluidicresistance of the inward part of the fluidic pathway (respectivelybetween the inlet port 9 and the valve 6) is at least ten times largerthat the fluidic resistance of the downward part of the fluidic pathway(that comprises the cavity, the outlet through hole 60 and the outletport 10). The obvious corollary is that the fluidic resistance of thecavity, which depends on reservoir pressure, should be at least tentimes smaller that the fluidic resistance of the inward fluidic pathwaywhatever the reservoir pressure.

In a first approximation, the flexible part of the membrane is thereforesubmitted to a gradient of pressure equal to the difference between thereservoir pressure and the outlet pressure.

Any change of the reservoir pressure induces a change of the valveopening and therefore to their fluidic resistances. For such annularvalves, and according to the discussion in the state of the artparagraph, the fluidic resistance of such valves is not linear butvaries as the power of −3 with their opening height. The use of only onevalve is not sufficient to offer the possibility of the constant flowrate or any specific flow profile when the reservoir pressure changes.

To get a constant flow rate over a given range of pressure, it isnecessary to implement at least two valves that are closed gradually butnot at the same rate when increases the reservoir pressure. In practice,the valve located near the center of the membrane will be closed firstwhile the valves located near the edge of the membrane need higherpressures to shut off.

The presence of at least two passive valves having variables fluidicresistances as varies the reservoir pressure is the main feature of thepresent invention. The first and second preferred embodiments of thepresent invention illustrates two differents ways to obtain such passivevalves.

The regulating range of pressure of the device is defined by thebehavior of the valves and their sensibility to pressure.

The range of flow rate depends on the fluidic resistance of the inwardfluidic pathway between the reservoir and the valve 6. Large fluidicresistances are required to obtain small flow rate.

The channels 8 are the second major feature of the present invention asdepicted FIG. 2 a: because these channels are decoupled to the valvesthemselves, they can be as long or as tight as necessary to reach highfluidic resistances.

The stress limiters 130 and/or 131 are the third major features of thepresent invention as depicted FIGS. 10 and 12: because the stress in themembrane is limited at high pressure, it is not necessary to use only amaterial having a very high yield strength like silicon: the use ofmetal or hard plastic is made possible by these stress limiters,inducing a significant reduction of the cost of the device.

In the two preferred embodiments of the present invention, the directionof the flow in the inlet ports 9 and outlet ports 10 is perpendicular tothe membrane plane as shown FIG. 1 b.

As shown FIG. 2 b, the channels 18 can be made in the pillar plate 14and in that case, the bottom substrate 3 is simply made of a flat platewith through holes 12.

As shown FIG. 2 c, the channels 19 can be made in both pillar plate 2and bottom plate 3.

A recess cavity 21 is etched in the membrane 1 as shown in FIGS. 1 a and1 b while the recess cavity 20 is made by etching the pillar plate 2 asshown in FIGS. 2 a and 2 b.

The height of the recess cavity 20 or 21 defines the gap 7.

Except the outlet, the whole device can be connected to the pressurizedfluid. A thin protective membrane 34 (see FIG. 4 a), typically apolymeric film, can be deposited onto the top surface of the membrane 1in order to prevent a free flow after the breaking of the membrane.

The pillar plate 2 and the bottom plate 3 can be made either in Pyrex orin silicon or in other materials including ceramic, plastic or metal.

Channels 8 and/or 18 and/or 19 are typically made of V-grooves obtainedby KOH etching of silicon substrate.

Channels 8 and/or 18 and/or 19 can be machined or directly obtainedduring embossing or injection.

Channels 8 and/or 18 and/or 19 are not limited to one street.

The through holes 208, 11, 12 and 60 can be obtained by dry etching,sand blasting, ultrasonic drilling or any other suitable technique.

The device can include means for measuring the deflection of themembrane 1, typically by implanting strain gauges into the siliconmembrane in a Wheatstone bridge configuration.

The critical parts that need a special care in terms of machiningtolerances are the membrane 1 thickness and flatness, the through holes208 diameters, the gap 7 and the channel depths 8, 18 and 19.

Since the pressure in the pillar cavity 4 should be very close to theoutlet pressure, the fluidic resistance of the outlet including eventualtubing or catheter should be ideally at least an order of magnitudelower than the other parts of the device independently of thefunctioning pressure.

The cross-section of the channels 8, 18 and 19 is typically triangular,rectangular or trapezoidal depending of the process used, but there isin fact no restriction for the cross-section shape.

There is at least one channel.

Each pillar 4 through hole can be connected to the same channel 8, 18and 19.

The typical device has at least one channel 8, 18 and 19 for each pillar4.

The channels 8, 18 or 19 should exhibit the main fluidic restriction ofthe device when the membrane 1 is not deflected. By increasing thepressure above the membrane 1, the resistance of each valve 6 increasesup to becoming larger than the resistance of the channel 8, 18 or 19 ata predefined pressure value for each valve 6.

The pillar substrate 31 may also include channel(s) 34, typically byusing a Silicon-On-Insulator (SOI) wafer as shown in FIG. 4 a. The oxide32 is used as an etch stop during the machining of the channel in theSOI layer 33.

The use of SOI for the pillar substrate can be desirable to improve thechannel depth machining accuracy because the oxide is a very efficientetch stop.

FIG. 4 a shows a first simplified view of the third embodiment of flowregulator based on a SOI pillar plate 31.

Depending on the process yield, all the critical parts may be includedinto the pillar plate 36 as shown FIG. 4 b (e.g. SOI design shownhereafter with the recess 20 etched in the pillar plate 36). Themembrane 1 is a simple flat plate without any machining while the bottomplates 3 is another simple flat plate only drilled in order to make theinlet through holes 12. The outlet port 10 could be a connector attachedby any means including gluing to the bottom plate 3.

FIG. 4 c shows a third simplified view of the third embodiment of thepresent invention, wherein both membrane 38 and pillar plates 36 aremachined to create the gap 7.

The pillar plate 37 may also contain no critical part as shown in FIG. 4d. The channel may be obtained by using again by using an SOI wafer forthe bottom plate 39.

In another embodiment the device is only made of two plates, themembrane 1 and the pillar plate 2, and flow restrictors 46 (channels forinstance) are placed into dedicated chips connected to the pillar plate2 using tubing 44, connectors 47 or other fluidic routing. This anotherembodiment may increase the dead volume (and therefore the primingduration) and the complexity of the assembly. The main advantage is thepossibility to use commercial off-the-shelf flow restrictors which canbe easily tested before assembly. Each restrictor can be simply made oftubing having a small internal diameter 48. Each restrictor can be madeusing the same gauge of tubing by simply adjusting its length to reachto targeted resistance.

As for the second preferred embodiment of the present invention, thefluidic resistances of the through holes 11 in the pillar plate can alsobe adjusted so as to ensure a flow regulation in the expected range ofpressure.

FIG. 5 represents a cross-section of device according to this anotherembodiment of the present invention, comprising a membrane 1 having arecess 21, a pillar plate 2 with through holes 11 and inlet connectors47. Three different types of flow restrictors are also illustrated inFIG. 5, respectively flow restrictors communicating 46 with the throughhole 11 of the pillar plate 2 using tubing 44, a flow restrictordirectly made in the pillar plate (through hole 11 itself), and finallya flow restrictor made of tubing 48 of small internal diameter.

The plates are linked together at specified linking areas 16 and 17,typically by anodic bonding (for Pyrex and silicon plates), by directbonding (for silicon plates), by Au—Au thermo-compression or by anyother suitable bonding technique.

An anti-bonding layer 51 may be deposited or grown, outside of thelinking areas, onto the membrane 1 backside. An anti-bonding layer 52can be also made onto the pillar plate 2 front side.

The FIG. 6 a shows a valve 6 according to the preferred embodiment ofthe present invention, wherein the anti-bonding layer is on the membrane1 back-side. The shape of the anti-bonding layer 51 is made to limit thesqueeze film effect, which occurs when two flat surfaces go intocontact. The anti-bonding layer 51 is preferably made of smalldimensions pads equally distributed over the whole surface of themembrane 1 (as shown FIG. 6 a) or the pillar plate 2 (as shown FIG. 6 b)or both. A specific anti-bonding shape 53 should be made for the valve 6in order to cover the entire valve seat.

Additional features for any of the previous embodiments of flowregulator:

-   -   Specific coating of the surfaces in contact with the liquid,        typically the membrane surfaces 80 and 81 or 70 and 71, the        cavity 5 more generally the whole fluidic pathway, to prevent        any corrosion of acid or basic solutions (e.g. TiO₂, . . . )    -   Coating of hydrophilic agents onto all surfaces in contact with        the liquid for better priming and lower surface contamination of        the device (e.g. PEG . . . )    -   Particle filter at the inlet to prevent valve leakage

A typical front view of a channel 8 of the preferred embodiment of thepresent invention is illustrated FIG. 7 a. This front view cancorrespond to the bottom plate 3 front-side as shown FIG. 2 a or thepillar plate 2 back-side as shown FIG. 2 b.

An inlet port 55 and an outlet port 56 are used to connect the channel 8or 18 to the through holes 11 and 12 of the pillar and bottom platerespectively. The dimensions of the ports 55 and 56 are mainly driven bythe alignment tolerances of the bonding process. The tight connectionshould be ensured and the alignment should not affect the fluidicresistance of the channel 8 or 18.

An example of a pillar plate front view 2 according to the preferredembodiment of the present invention is shown FIG. 7 b. The position ofthe outlet 60 with respect to the pillars 4 is mainly driven by theresistance of the fluidic pathway between the pillars and the outletwhich should be small with respect to other resistances. According tothis remark, the outlet 60 should be ideally placed near the pillar 4,which is linked to the channel 8 that shows the largest flowrestriction.

The maximum distance between each pillar 4 (with or without throughhole) is driven by the effect of the secondary deformation of thefreestanding part of the membrane 1 between those pillars at highpressure. This additional deformation should not modify the fluidicbehaviour of the device.

The pillar cavity 5 shown in the FIG. 7 b should be designed byconsidering the two former remarks, but also by considering the primingcapability of the device. The pillar cavity geometry will ideallyminimize the dead volume and ensure that the main stream travels throughthe largest part of this dead volume.

There is no limitation for the external shape of the device.

In another embodiment, the present invention concerns a flow regulatorof the passive type comprising a fluid inlet 9 adapted to be connectedto a fluid reservoir and a fluid outlet 10 adapted to be connected to adelivery location, said regulator comprising a pillar plate 101, abottom plate 3 and a membrane plate 100 having a recess 104 to define aflexible membrane 110, these three plates being tightly linked togetherin predefined linking areas 17 and 16 so as to define at least onecavity 5 and channels 8 therebetween, said cavity 5 being connected tosaid fluid outlet 10 by the through hole 60.

In this another embodiment of the present invention, said rigidsubstrate 101 has a first surface opposite to said cavity 5 which isconnected to said fluid inlet 9 and while said membrane 100 has anexternal surface opposite said cavity 5, said pillar plate 101furthermore having at least a through hole 11, said bottom plate havinga channel 8 and a through hole 12 contiguous with said through hole 11,to define a pathway for a fluid from said fluid inlet 9 to said fluidoutlet 10, said flexible membrane 110 being able to come into contactwith said pillar 4, of the pillar plate 101 within said cavity 5 andwith a portion including said through hole 11 and defining a valve 6, incase a fluid applies a pressure on said external surface that is largerthan a first predefined threshold value, which results in hindering afluid from flowing through said through hole 11 and said valve 6,wherein said pillar plate comprises at least one additional through hole114 in an additional cavity 115 contiguous to said cavity 5, wherein thefluid can flow from said additional cavity 115 toward the cavity 5 viaopenings 120, wherein said membrane plate 100 comprises at least anadditional flexible membrane 111, said additional flexible membranebeing able to come into contact with said pillar plate 101 onto thepillar 117, within said additional cavity 115 and with a portionincluding said additional through hole 114 and defining an additionalvalve 116, in case a fluid applies a pressure on said external surfacethat is larger than said first predefined threshold value but smallerthan a second predefined threshold value, said additional membrane 111,said additional cavity 115 and said additional through hole 114 beingfurther arranged so that a fluid flow rate is be substantially linear asa function of the pressure applied on said external surface in a rangegoing approximately from said first to said second predefined thresholdvalues.

A simplified side-view of this another embodiment of the presentinvention is shown FIG. 8 a, the regulator undergoing a first lowpressure. The same regulator undergoing a second higher pressure isillustrated FIG. 8 b.

A simplified pillar plate front view of one of the fifth embodiment isshown FIG. 9 a.

The membrane back-side (etched side) of this another embodiment is shownFIG. 9 b. Depending on the process used, the recess 104 or 105 may havea recess wall showing a slope. By using anisotropic wet etch on <100>silicon wafer, the typical recess wall angle is 54.7°.

The different cavities in the device should be interconnected as shownFIG. 9 a with the openings 120. Ideally, the fluidic resistances ofthese interconnections are designed to ensure that the pressure in allcavities is very close to the outlet pressure.

The membrane plate 100 can include membranes of any shape includingsquared, rectangular, elliptical and circular membrane. Membrane ofdifferent shapes can be made in the same membrane plate 100.

In the two preferred embodiments of the present invention, thedeformation of the membrane 1 against a pillar plate 2 is used. Thiseffect is strongly non-linear, resulting in a stiffening of the membrane1 by increasing pressure. To close a non-centred valve 6, a largepressure and or a wide and/or a thin membrane 1 is necessary. Valves canbe classified as low and high-pressure valves, i.e. a valve that isclosed at low (resp. high) pressure.

In the embodiment of the present invention depicted FIG. 8 a, thepillars 4 are placed in front of the center of the membranes 110. Inthat later configuration, the threshold is adjusted, from one valve toanother in the same membrane plate 100, by the dimension of the membraneand the distance between the membrane and the substrate. Thehigh-pressure valves of the first embodiment are replaced, e.g., byvalves having smaller membrane surface and/or thicker membranes. Toreduce the dimension of the low pressure membrane, the gap 7 (the depthof each recess cavity 104 in the membrane plate 100) is smaller than themembrane thickness.

In the preferred embodiments, reducing the gap 7 makes the contactradius of the membrane 1 on the pillar plate 101 increasing very quicklyat low pressure, and therefore central part of the membrane 1 is onlyused to regulate a small range of low pressure. This explains why thepillars 4 are significantly decentred by design.

The design of the embodiment depicted FIG. 8 a allows a larger range ofoperating pressures and a better accuracy over the whole range becausehigh-pressure and low-pressure valves can be embedded into the samedevice. It is however important to take care of the physical integrityof the low-pressure valve at high reservoir pressure: the yield strengthof the material should not be reached otherwise plastic deformation willbe observed, leading to a change of the fluidic behaviour of the device.

The membrane of the preferred embodiments is preferably made of silicon,first of all because of its very high yield strength but also becauseMEMS techniques allow good machining tolerances for the through holesand channels. There is a strong interest of using a cheaper membranematerial like plastic: for cost reason by also for the simplification ofthe process and the possibility to make in a simplified manner membraneshaving different thicknesses and gap having different heights.

The embodiment depicted FIG. 8 a, which can be made in plastic, would bemade of:

-   -   A non-drilled membrane plate 100    -   A pillar plate 101 having large through holes 11, pillars 130        and steps 131 for the limitation of the membrane 100 stress at        high pressure    -   A channel plate 3 having through holes 12 and channels 8.

As for the preferred embodiments of the present invention, the numberand the dimension of the valves are adjusted to match the requiredaccuracy and flow regulated pressure range.

The concepts of stress limiter pillars 130 and steps 131 (SLP/SLS) areillustrated FIG. 10 hat shows a valve 6 of the fifth embodiment of thepresent invention. The valve 6 comprises here both stress limiters, butin a preferred embodiment, only one type of stress limiter is used,typically the step because the dead volume of the device is smaller.Only one valve 6 is shown FIG. 10 for sake of clarity; the device caninclude several valves depending of the range of pressure. The centre ofthe membrane 100 reaches first the pillar 4 with the through hole 11 andcloses the valve 6. By increasing the reservoir pressure, the membrane100 goes into contact with the stress limiter step 131 and/or the pillar130 or both. The additional bending of the membrane is limited thanks tothis mechanical support. By using pillars 130 instead of steps 131,openings 135 should be included to avoid air trapping. The SLP shouldtherefore not have the perfect cylindrical symmetry as shown FIG. 11.

The SLP 130 or SLS 131 or both are positioned and designed to ensurethat the yield strength of the membrane material is not reached duringthe functioning of the device. Several steps or pillars may be used.

The SLP 130 or SLS 131 have typically a height larger than the pillar 4having the through hole 11.

The channel 18 is preferably included into the pillar plate. Thechannels 18, the pillars 4 and 30, the steps 131 and all parts of theplastic plates should respect the standard design rules of molding orembossing (adapted clearance angles . . . ).

In another embodiment of the present invention, the SLP 145, the valvepillar 145 and the cavity 150 are machined in the membrane backside 140as shown FIG. 12. The pillar plate 142 has no longer pillar but stillthrough holes 11 (also named through holes in the text).

Gluing, soldering, fusion bonding or any other bonding techniques can beused to assemble the different plates using the predefined linking areas16 and 17. The plates can be made of different materials, for instancethe membrane 1 or 100 or 140 could be made of silicon while the pillarplate 2 or 101 or 142 and the bottom plate 3 are made of plastic. Anycombination of material can be considered. The compatibility betweenthese materials and the fluid to be injected should be considered. Thewater absorption of the materials should not affect the fluidicbehaviour of the device, typically if plastic materials are used.

An another embodiment of the present invention is depicted FIG. 13 a.This embodiment is directly derived from the second preferred embodimentof the present invention, wherein there are additional steps 131.

This another embodiment comprises therefore at least two plates:

-   -   A membrane plate 1 having at least two through holes 208    -   A pillar plate 2 having an outlet through hole 60, pillars 4 and        steps 131.

A simplified view of a valve 6 of this another embodiment is shown FIG.13 a.

By placing another pillar plate 222 above the drilled membrane 1, it ispossible to make a bidirectionnal flow regulator. The FIG. 13 billustrates a bidirectional valve made of two valves 6 and 230. Anotherembodiment of the present invention comprises at least 2 bidirectionalvalves.

The number of valves is adjusted by design to meet the accuracy budgetof the device, the range of pressure and the device dimensions. Thebi-directional flow regulator shown FIG. 13 b is symmetric.

The FIG. 13 c illustrates a simplified view of asymmetric valves 6 and237 as an element of another embodiment of the present invention. Thevalve 237 is a check-valve with a pillar 229 placed in a cavity 261which is connected to the pressurized reservoir via the through hole 200in the plate 222. The pillars 229, which may have an anti-bonding layer233, are here in contact with the membrane when the reservoir is notpressurized.

Depending of the height of the pillar 223 and the anti-bonding layerthickness it is possible at adjust the threshold of the check-valve 237.

Any of the previous embodiments can advantageously include a switch thatallows selecting externally the channels 8 in order to change the flowrate. The switch can be made, for instance, of a polymeric layer 310with openings 311 and a hole for the inlet 312. By rotating and pushingthe film 310 against the bottom plate 300, some channels 8 become openwhile other ones become closed.

The FIG. 14 a illustrates the corresponding backside of the bottom platewith three series of aligned through holes 302, 303 and 304respectively. Each series of through holes can be seen as an individualregulator. We can consider for instance that the three series of throughholes 302, 303 and 304 corresponds to three regulators having nominalflow rates of 1, 2 and 4 ml per hour respectively. The outlet 301 of thebottom plate 300 will be preferably located at the centre of the film310 for symmetry evidence. The channels are located here at theinterface between the pillar plate 2 and the bottom plate 3. Forembodiments having no bottom plate, the FIG. 14 a corresponds to thebackside of the pillar plate 2.

The FIG. 14 b illustrates a film 310 with radial openings 311 (slits)and opening 312 (hole) at its centre.

The film 310 can be assembled on the bottom plate 300 using mechanicalclamps, screws, clips or other standard assembly means. For theembodiments only made of a membrane and a pillar plates, the film isdirectly applied on the pillar plate.

For the fourth embodiment of the present invention that is only made ofa membrane and a pillar plates, the film is directly applied on thepillar plate.

For the seventh embodiment of the present invention that is only made ofa drilled membrane and a pillar plates, the film is directly applied onthe membrane plate.

The FIG. 14 c shows the film 310 aligned with the bottom plate 300 tolet all through holes 302, 303 and 304 opened. In the laterconfiguration, the total flow rate is the sum of the nominal flow rateof the three series of through holes. According to the former example,the flow rate is therefore 7 ml per hour. By rotating the film, thetotal flow rate can be set to 1 to 7 ml per hour by combination of thethree nominal flow rates. The arrows 320 around the film indicate theposition of the film that leads to the required flow rate.

Considering any of the preceding embodiments comprising at least onehole in a pillar or a membrane that is not intended to be closed at highpressure, the outlet shall be located very close to said hole in orderto reduce first the fluidic resistance but also to prevent the presenceof any residual bubble that should block said hole.

Because the different embodiments of the device are intended first toregulated rather low flow rate (typically few ml per hour), the primingcapability of the devices is a major concern. The design shall minimizethe air trapping area wherein the flow rate is very small. The deadvolume (typically the cavity 5) shall be also optimized as shown FIG. 7b wherein the cavity 5 is limited to the area surrounding the holes ofthe fluidic pathway.

The device can advantageously include a protective cap and a fluidicswitch as depicted FIGS. 15 a and 15 b in order to reduce the primingduration. The embodiment depicted FIG. 2 a, which is one of thepreferred embodiments for low flow rate regulation, has been used toillustrates these new features.

The protective cap 440, made in a hard material, e.g. Pyrex™ or silicon,is tightly linked to the surface 80 of the membrane 1 in predefinedlinking areas 430 having the same layout that the linking areas 16. Theprotective cap 440 has a cavity 441 above the flexible part of themembrane 1 except on pillars 443 wherein an antibonding layer 442 ismade to prevent any bonding between the pillars and the membrane 1. Thepillars are in contact with the membrane and therefore only thedisplacement of the membrane towards the pillar substrate is possible.The protective cap has at least one fluidic port 444 which is connectedto the cavity 441 because the pillars 443 are not in contact betweeneach others. Only two pillars are shown FIGS. 15 a and 15 b but there isno limitation on the number or the shape or the disposition of thepillars.

The fluidic port 444 is connected to the reservoir of the device via afluidic pathway made of a fluidic line 412, a fluidic switch 420 and afluidic line 411 between the reservoir and the switch.

The inlet ports 9 of the device are connected to the reservoir viaanother fluidic pathway made of a fluidic line 413, a fluidic switch 420and a fluidic line 411 between the reservoir and the switch.

In FIG. 15 a the switch is placed in position 1 which corresponds to thepriming position: the reservoir is filled and the pressure rises up toP_(reservoir). The fluid can flow from the reservoir to the device viathe line 413 while the line 412 and the cavity 441 of the protective capare not pressurized. The membrane does not deflect towards the pillarand all valves 6 are open even at high pressure, inducing a high flowrate in the device and therefore faster priming. The pillars 443 preventthe breaking of the membrane when too large pressure is applied in thereservoir when the switch is in position 1. When the priming is finished(when the fluid flows at the outlet 10), the switch is turned inposition 2 which corresponds to the infusion position as shown FIG. 15b. The reservoir pressure is not present both at the inlet ports 9 andthe cavity 441, and the device can now regulate the flow according toits intended use.

In order to reduce the priming duration, a syringe (not representedhere) can be used to generate the high priming pressure: the syringe canbe plugged directly onto the switch in position 1 and the user can thenprime the device by pressing onto the syringe plunger. The syringeshould then be removed and replaced by the reservoir.

The switch may include other positions, for instance a pressure releaseposition to vent the lines 412 and 143 or a position that isolates thereservoir from both inlet ports 9 and protective cap 440 (notrepresented in FIGS. 15 a and 15 b).

Any of the previous embodiments can advantageously include at least anactive valve. The active valve can be made of an actuator linkedpermanently to the membrane or simply during the actuation. The valvemay include a conductive or magnetic layer to that end. Various types ofactuators can be used:

-   -   Piezo    -   Electrostatic    -   Shape Memory Alloy    -   Shape Memory Polymer    -   Electromagnetic . . . .

The active valve can be used to regulate the flow (duty cycle mode) orsimply as a safety valve that closes or opens the valve under predefinedconditions. To that end, the active valve may be advantageouslyconnected to a pressure or flow rate sensor.

Nonrestrictive examples of regulation profiles are given below for thepreferred embodiment of the present invention:

-   -   Constant flow rate in a predefined range of pressure.    -   An opening threshold at low pressure, a constant flow rate in an        intermediate range of pressure and a shut-off at high pressure.    -   Hydrocephalus like profile having an opening threshold at low        pressure, a constant flow rate in an intermediate range of        pressure and a free flow at high pressure.

The preferred embodiment of the present invention is based on theelastic deformation of a flexible membrane. FEM simulations arenecessary to estimate the shape of the membrane at the differentfunctioning pressures.

The pillars (drilled or not) support the deflected membrane. A correctrepartition of the pillars ensures an axi-symmetric deformation of thepressurized membrane.

Model for the Preferred Embodiment of the Present Invention:

We consider a device as depicted in FIG. 2 a. Basically, there are twomain fluidic restrictions in the device:

-   -   1. The channels.    -   2. The valves.

All other parts of the fluidic pathways should be negligible in term offluidic resistance by design. The pillar cavity is therefore designed tomeet this requirement as well as the through holes and outlet diameters.

Notations:

-   Dynamic viscosity of the fluid η-   Fluid volumetric mass ρ-   Young modulus E-   Membrane thickness t_(m)-   Hole radius R_(h)-   Hole depth L_(h)-   Pillar radius R_(p)-   Distance between the pillar i and the membrane (valve opening    height): h_(i)-   Pressure gradient ΔP=P_(in)−P_(out)-   Flow rate via the fluidic pathway i: Q_(i)-   Channel width w_(c)-   Channel height h_(c)-   Channel length L_(c)-   Fluidic resistance R_(f)-   Fluidic resistance of a channel R_(fc)-   Fluidic resistance of a valve R_(fv)-   Fluidic resistance of the outlet Rf_(out)

The flow can be modelled as fluidic resistances in series for thechannel and the valve, each couple of channel and valve being placed inparallel between each other (same inlet and same outlet). We assume theflow is laminar.

Rectangular channels are considered here. The fluidic resistance R_(f)of the channel i is:

$R_{{fc}_{i}} = \frac{12\eta \; L_{ci}}{w_{c}{h_{c}^{3}\left\lbrack {1 - {\frac{192h_{c}}{\pi^{5}w_{c}}{\sum\limits_{{j = 1},3,5,\ldots}^{\infty}\frac{\tan \; {h\left( {{j\pi}\; {w_{c}/2}h_{c}} \right)}}{j^{5}}}}} \right\rbrack}}$

For w_(c)>>h_(c) (flat channel):

$R_{{fc}_{i}} = \frac{12\eta \; L_{ci}}{w_{c}h_{c}^{3}}$

Fluidic resistance Rfv_(i) of the valve i:

${Rfv}_{i} = {\frac{6\eta}{\pi \; h_{i}^{3}}l\; {n\left( \frac{R_{p}}{R_{h}} \right)}}$

The flow rate Q takes the form:

$Q = {{\sum\limits_{i}Q_{i}} = {\Delta \; P{\sum\limits_{i}\frac{1}{{Rfc}_{i} + {Rfv}_{i}}}}}$

If the Reynolds number become much larger than one at the givenpressure, the singular head losses shall be considered.

Singular head losses are proportional to the square of the flow rate andtherefore we should consider them at high flow rate. It is important tonote that the reversibility of the flow is no longer valid. We shouldconsider the fluidic pathway in both directions.

The difference of pressure ΔP=P_(in)−P_(out) is written as a function ofQ_(i) as follow:

ΔP=α _(i) Q _(i) ²+β_(i) Q _(i)

Where i indicates one fluidic pathway,

$\beta_{i} = {\sum\limits_{i}{Rf}_{i}}$

is the sum of the fluidic resistance of the fluidic pathway I and α_(i)is a function of the surfaces of each singularity.

We estimate numerically the function for α_(i)Q_(i) for each value ofΔP:

${\alpha_{i}Q_{i}} = {{- \frac{\beta_{i}}{2}} + \sqrt{{\alpha_{i}\Delta \; P} + \frac{\beta_{i}^{2}}{4}}}$

The total flow rate is therefore:

$Q = {\sum\limits_{i}Q_{i}}$

To simplify the formulation, we consider that the channels 8 have theshape of a hole. We consider in the general case all contributions tothe fluidic resistances including outlet through hole 60 and cavities 5.For positive gradient of pressure, the fluid flows therefore through thechannel 8 (here a hole), the valve 6, the cavity 5 which is assimilatedto a fluidic channel and finally the outlet through hole 60 (having alsothe shape of a hole), the parameters α_(i) and β_(i) take the form:

$\quad\left\{ \begin{matrix}{\alpha_{i} = {\frac{\rho}{2}\left( {\frac{1.4}{\pi^{2}R_{hi}^{4}} + {\frac{1}{4\pi^{2}h_{i}^{2}R_{pi}^{2}}\left( {1 - \frac{h_{i}}{h_{c}}} \right)^{2}} + \xi_{i}} \right)}} \\{\beta_{i} = {\frac{8\eta \; L_{hi}}{\pi \; R_{hi}^{4}} + {\frac{6\eta}{\pi \; h_{i}^{3}}l\; {n\left( \frac{R_{hi}}{R_{pi}} \right)}} + \frac{12\eta \; L_{ci}}{w_{ci}h_{ci}^{3}}}} \\{\xi_{i} = {{\frac{1}{\pi^{2}R_{hi}^{4}}\left( {1 - \frac{R_{hi}}{2h_{i}}} \right)^{2}\mspace{11mu} {if}\mspace{14mu} R_{h}} \leq {2h_{i}}}} \\{\xi_{i} = {{\frac{1}{10\pi^{2}h_{i}^{2}R_{hi}^{2}}\left( {1 - \frac{2h_{i}}{R_{hi}}} \right)\mspace{14mu} {if}\mspace{14mu} R_{h}} \geq {2h_{i}}}}\end{matrix} \right.$

For negative gradient of pressure, i.e. when the fluid flows through theoutlet through hole 60, the cavity 5 (channel) up to the valve 6 andfinally the channel 8 (hole), the parameters α and β take the form:

$\quad\left\{ \begin{matrix}{\alpha_{i} = {{\frac{\rho}{2}\left( \begin{matrix}{{\frac{1}{10\pi^{2}h_{i}^{2}R_{pi}^{2}}\left( {1 - \frac{h_{i}}{h_{c}}} \right)} +} \\{\frac{1}{4\pi^{2}h_{i}^{2}R_{pi}^{2}} + \frac{1}{\pi^{2}R_{hi}^{4}} + \xi_{i}}\end{matrix}\; \right)} = {\frac{\rho}{2}\begin{pmatrix}{{\frac{1}{4\pi^{2}h_{i}^{2}R_{pi}^{2}}\left( {1.4 - \frac{h_{i}}{h_{c}}} \right)} +} \\{\frac{1}{\pi^{2}R_{hi}^{4}} + \xi_{i}}\end{pmatrix}}}} \\{\beta_{i} = {\frac{8\eta \; L_{hi}}{\pi \; R_{hi}^{4}} + {\frac{6\eta}{\pi \; h_{i}^{3}}l\; {n\left( \frac{R_{hi}}{R_{pi}} \right)}} + \frac{12\eta \; L_{ci}}{w_{ci}h_{ci}^{3}}}} \\{\xi_{i} = {{\frac{0.4}{\pi^{2}R_{hi}^{4}}\left( {1 - \frac{R_{hi}}{2h_{i}}} \right)\mspace{20mu} {if}\mspace{14mu} R_{h}} \leq {2h_{i}}}} \\{\xi_{i} = {{\frac{1}{4\pi^{2}h_{i}^{2}R_{hi}^{2}}\left( {1 - \frac{2h_{i}}{R_{hi}}} \right)\mspace{14mu} {if}\mspace{14mu} R_{h}} \geq {2h_{i}}}}\end{matrix} \right.$

We consider also a fluidic resistance at the outlet Rf_(out) (e.g. theinfusion line). In that case, for a given pressure gradient ΔP, weestimate the flow rate Q as shown previously. The additional pressuredrop ΔP_(out) due to Rf_(out) is then:

ΔP _(out) =Rf _(out) Q

The effective gradient of pressure necessary to get the flow rate Q istherefore:

ΔP _(eff) =ΔP+ΔP _(out)

The functions h_(i)(P) are estimated using the FEM model for themembrane deformation under pressure.

A detailed description of the embodiment depicted FIG. 9 a(multimembrane design) is provided here. We assume the gap is no largerthan 0.4 times the width of the membrane. In that configuration thedeflection up to the contact is linear with pressure.

An analytical model is used to estimate the flow rate versus pressurecharacteristic of the device.

To simplify the formula of the membrane deflection under pressure, wedesign a device having pillar plate and a membrane plate made ofcircular membrane and circular holes.

The flow can be modelled using simply fluidic resistances in seriesincluding the holes and the opening between the pillars and themembrane.

The distance h_(i)(P) between the membrane centre i and the pillar i atthe pressure P (opening height of the valve i) is:

${h_{i}(P)} = {{h\left( P_{0} \right)} - \frac{\Pr_{m\; i}^{4}}{64D}}$With $D = \frac{{Et}_{m}^{3}}{12\left( {1 - \upsilon^{2}} \right)}$

For P<P_(contact) i, where P_(contact) i is the contact pressure of themembrane i against the pillar i, h(P₀) is the initial gap height(=recess height), D is the plate constant, r_(m i) the radius of themembrane i, t_(m) the membrane thickness and ν the Poisson's ratio ofthe membrane material.

For P>P_(contact i),

h _(i)(P)=0

Flow Regulation at 4 Ml/day for a 4-Membrane Silicon Regulator

The flow regulator can be used for pain management. Smaller flow ratesare expected, typically 1 ml per hour or less. To avoid overdoses, thedevice should be a shut-off valve at high pressure.

A silicon device having four membranes and four channels have been usedfor the following simulation. Such valves without the features 130 and131 are illustrated FIG. 10. The device may also be obtained using asingle membrane with still several channels and several pillars belowsaid membrane according the embodiment depicted FIG. 2 a or 2 b or 2 c.In all cases the number of membranes or the number of pillars below thesame membrane may be varied depending on the targeted flow rate andaccuracy.

Device Parameters:

-   -   Silicon membranes    -   Young modulus 170 GPa    -   Poisson coefficient 0.262    -   Thickness 50 microns    -   Gap 20 microns        Channel parameters:    -   Depth 2.5 microns    -   Width 100 microns

The dynamic viscosity is 0.0007 Pa·s at 37° C.

The channel lengths have been adjusted to match the flow rate of 4 mlper day between 200 and 400 mbar. The table 1 summarizes the maindimensions of the device:

TABLE 1 dimensions of a silicon regulator for drug infusion at 4 mlperday Diameter (mm) Channel length (mm) pillar diameter (um) 5.43 1.97300 5.81 23.9 300 5.98 15.02 300 6.23 9.48 300

FIG. 16 represents the simulated relationship between the flow rate andthe pressure.

The main error on the flow rate accuracy for a flat channel is mainlydue to the error on the depth. Using Silicon-On-Insulator, an error of+/−0.05 micron at 1σ(=+/−2% for a depth of 2.5 microns) can be achievedon the channel depth, leading to an error of about +/−6% at 1σ on theflow rate accuracy. The error due to the lateral etching of the channelis about +−0.33% (100+/−0.33 microns at 16) and can be neglected.

The microchannels introduce here an error of +/−6% at 1σ on the flowrate accuracy.

For instance, the following specifications would apply for a flowregulator according to invention, which is embedded into an implantablepump for analgesics delivery:

-   -   a) Constant flow rate of 1 ml/day    -   b) Liquid equivalent to water in term of viscosity    -   c) Temperature=37° C.    -   d) Range of pressure=200 to 400 mbar

The same device can be made using a membrane having holes in front ofthe pillars as depicted in FIG. 1 b or 13 a. To match the flow rate of 4ml per day, using the two same membranes and gap of 20 microns, theholes should exhibit a diameter of respectively 6.81 um, 3.3 um, 4.3 umand 4.6 um. The very small dimensions of the holes indicate that thisdesign is not well adapted to low flow rate because the machiningtolerances of the holes limit strongly the flow rate accuracy of thedevice.

This example illustrates the interest of the embodiments of the presentinvention that comprise channels 8 or 18 or 19 to generate the flowrestriction instead of tiny holes) for low flow rate regulation.

The flow regulators previously exposed can be embedded into animplantable pump that contains:

-   -   A titanium housing    -   A drug reservoir    -   Filling ports for the drug    -   A catheter port    -   A catheter access port for bolus injection    -   A pump drive    -   A temperature sensor    -   A flow regulator    -   A filter (e.g. bacterial filter with pore size of 0.22 micron)    -   A controlled valve    -   Batteries to power the valve, the temperature sensor and the        pressure sensor    -   Wireless system to power the pressure sensor and the temperature        sensor    -   Alarm system that indicates:        -   Low batteries        -   Empty drug reservoir        -   Over or under pressures (out of the regulated pressure            range)    -   Membrane Break        -   Overheating

The flow regulator according to the present invention offers inparticular the following advantages:

-   -   Lower risks of under and over dose due to pressure changes        (climbing, diving . . . )    -   No risk of explosion if no gas propeller is used    -   Lower risk during the fill refill procedure    -   No risk of overdose during impact to the body in the pump of the        pump

Flow Regulator for Hydrocephalus

A device dedicated to hydrocephalus has been also designed in silicon(Young Modulus of 170 GPa and Poisson's ratio 0.262) and PMMA (YoungModulus of 3 GPa and Poisson's ratio 0.35).

The regulation profile has been set to regulate the flow rate at 20 mlhbetween 15 and 40 mbar. The high flow rate makes possible the use ofhole in the flexible membrane instead of a channel connected to adrilled pillar.

The device is therefore made of 2 plates in silicon or PMMA:

-   -   A membrane plate having 2 membranes having one hole at their        centres; one membrane has also an additional hole near the edge        of the membrane.    -   The outlet and the pillars are made in the bottom plate

The fluid pressure directly applies on the top surface of the membrane.The pillars and the membranes have here the same dimensions for bothdesigns. For plastic device these dimensions may be variable inside thesame regulator. Grey arrows indicate the flow direction. A valve of thelater device according to the seventh embodiment of the presentinvention is illustrated FIG. 13 a.

The critical dimensions of the silicon and PMMA devices are shown in theTable 2 and 3. The third hole is located on the edge of a membrane whilethe two other membrane holes are centred.

TABLE 2 dimensions of the silicon valve for hydrocephalus. MembraneMembrane Hole Pillar diameter thickness Gap diameter diameter (um) (um)(um) (um) (um) 9250 50 20 69.5 (centre) 166 10750 50 20   79 (centre)179 63.5 (edge) 150

TABLE 3 dimensions of the PMMA valve for hydrocephalus. MembraneMembrane Hole Pillar diameter thickness Gap diameter diameter (um) (um)(um) (um) (um) 3550 50 20 72 (center) 145 4100 50 20 55 (center) 100 67(edge) 150

The surface of the PMMA device is more than 6 times smaller than thesimilar device made of a single membrane in silicon.

The flow characteristics have been simulated and the graphs are shown inFIGS. 17 and 18 for the silicon and the PMMA devices respectively.

Depending on the mechanical, chemical and biocompatibility requirements,other plastic materials can be used like SAN, COC, PC . . . .

The invention is of course not limited to the above cited examples andrelated figures. There is for instance no limitation to the number andthe distribution of the valves, through holes, pillars and the channels.The shapes of the pillars, stress limiter features, through holes,membranes and pads for the anti-bonding layer or channels are notlimited to the above cited examples.

1. Flow regulator comprising a fluid inlet adapted to be connected to afluid reservoir and a fluid outlet adapted to be connected to a deliverylocation, said regulator comprising a rigid substrate and a flexiblemembrane tightly linked together in predefined linking areas, saidsubstrate and/or said membrane having a recess so as to define—when saidmembrane is in a rest position—a cavity between said membrane and saidsubstrate; said substrate and/or said membrane having a through holecontiguous with said cavity and communicating with said fluid outlet,said substrate and/or said membrane furthermore comprising twoadditional through holes contiguous with said cavity and communicatingwith said fluid inlet; said substrate and/or said membrane having atleast two pillars within said cavity, the height of each of said pillarsbeing such that, when said membrane is at rest, a gap is formed betweenthe pillar free end and the opposite cavity wall; each of said pillarsbeing furthermore aligned with one of said additional through holes andforming a valve in said gap; said pillars furthermore having a widththat is larger than the width of said aligned through hole; saidflexible membrane being able to come into contact with at least a firstpart of said substrate, within said cavity and with a portion includinga first of said valves, in case a greater pressure than a firstpredefined threshold value is applied on the surface of the membraneopposite to the said substrate, which results in lowering said gapheight up to zero and hindering a fluid from flowing through said firstvalve, said flexible membrane being able to come into contact with atleast a second part of said substrate, within said cavity and with aportion including a second of said valves, in case a pressure largerthan a second predefined threshold value is applied on the surface ofthe membrane opposite to the said substrate, which results in hinderinga fluid from flowing through said second valve, wherein the pillars andthe additional through holes positions and dimensions are arranged sothat the fluid flow rate is passively regulated at least in a range ofinlet pressure going from said first and said second predefinedthreshold values.
 2. Flow regulator according to claim 1, comprising nadditional pillars in said cavity, said substrate and/or said membranecomprising at least n additional though holes contiguous with saidcavity, communicating with said fluid inlet, and forming n valves, eachi-th valve being arranged such that the fluid may flow through it incase a pressure smaller than a i-th predefined threshold value isapplied on the surface of the membrane opposite to the said substrate,said n valves being further designed and arranged so that the fluid flowrate is passively regulated at least in a range of inlet pressure goingapproximately from said first and said (n+2)-th predefined thresholdvalues.
 3. Flow regulator according to claim 1, comprising a bottomplate tightly linked to the pillar plate in predefined linking areas,said bottom plate comprising through holes communicating with saidadditional through holes of the substrate and with the fluid inlet,defining a fluidic pathway from the inlet to the outlet made of theinlet connected to said fluid reservoir, said through holes in thebottom plate, said additional through holes in the substrate, saidvalve, said cavity and said through hole communicating with the outlet.4. Flow regulator according to claim 1, comprising at least one flowrestrictor which is communicating with at least one of said additionalthrough holes of the substrate, wherein said flow restrictor has afluidic resistance larger, in a predefined range of pressure, than thefluidic resistance of the other parts of the fluidic pathway.
 5. Flowregulator according to claim 3, wherein the interface between saidsubstrate and said bottom plate contains a channel plane in which atleast one channel is defined, said additional through holes of thesubstrate and said through holes of the bottom plate communicating viaat least of said channel and wherein said channel has, in a predefinedrange of inlet pressure, a fluidic resistance larger than the fluidicresistances of the other parts of the fluidic pathway.
 6. Flow regulatoraccording to claim 5 wherein said interface between the substrate andthe bottom layer is a layer of Silicon-on-Insulator.
 7. Flow regulatoraccording to claim 1, wherein at least one of said valve is a shut-offvalve and/or a check-valve.
 8. Flow regulator according to claim 1,wherein the linking areas between said membrane and said substratedefines m flexible parts of the membrane and m cavities between said mflexible parts of the membrane and said substrate, said m cavities beingcommunicating between each other and with a common through holeconnected to the outlet, each of said m cavities comprising at least onepillar, one through hole connected to the inlet and therefore at leastone valve, each j-th valve being arranged such that the fluid may flowthrough it in case a pressure smaller than a j-th predefined thresholdvalue is applied on the surface of the membrane opposite to the saidsubstrate, said m valves being further designed and arranged so that thefluid flow rate is passively regulated at least in a range of inletpressure going approximately from said first and said (m+2)-thpredefined threshold values.
 9. Flow regulator according to claim 8,wherein the thickness and/or the diameter or both of each said mflexible part of the said membrane and/or the height and the diameter orboth of each of the m pillars and/or the height of said m cavitiesand/or the diameter of each m through holes are variable.
 10. Flowregulator according to claim 1, comprising in said cavity at least onefull pillar, i.e. devoid of any through hole, and/or at least one step,wherein said full pillar and/or said step are not forming part of a saidvalves, and wherein said pillar and for said step limit the deflectionand the stress of the membrane in case a pressure larger than apredefined threshold value is applied.
 11. Flow regulator according toclaim 1, comprising an additional plate tightly linked to the membranein predefined linking areas, wherein said additional plate and/ormembrane has recess to form a additional cavity between said membraneand said additional plate, said additional plate comprising a throughhole connecting the pressurized reservoir to said additional cavity,wherein said additional plate comprises at least one pillar in front ofsaid through holes in the membrane, said pillar closing said throughhole in the membrane in a predefined range of pressure, preventingtherefore a back-flow in said through hole.
 12. Flow regulator accordingto claim 1, comprising an additional plate tightly linked to themembrane in predefined linking areas, wherein said additional plate andor membrane has recess to form an additional cavity between saidmembrane and said additional plate, wherein said additional platecomprises at least one pillar that prevent the deflection of themembrane in the direction of said pillar, wherein said additional platecomprises a through hole connected to the said additional cavity, saidflow regulator comprising a fluidic switch having at least three portsincluding a first port communicating with said fluid reservoir, a secondport communicating with said through holes of the bottom substrate athird port communicating with said through hole in the additional plate,wherein the fluid flows only from the reservoir to the through holes ofthe bottom substrate when the switch is one a first position that allowsthe communication between the ports 1 and 2 while the port 3 is closed,preventing the application of the reservoir pressure in said cavitybetween said membrane and said additional plate and therefore thedeflection of said membrane to close said valves, and wherein all portsof the switch are communicating between each other when the switch is ina second position, said additional cavity being therefore submitted tothe reservoir pressure, allowing the fluid to flow from the reservoir tothe through holes of the bottom substrate and allowing the displacementof the membrane and therefore the closure of the valves as varies thereservoir pressure.
 13. Flow regulator according to claim 1, comprisinga thin resilient polymeric layer above the surface of said membraneopposite to the said substrate.
 14. Flow regulator according to claim 1,comprising a resilient and removable film on the bottom plate sideopposite to the substrate and/or above the surface of said membraneopposite to the said substrate, said film having openings to selectivelyopen or close one or several of said valves depending on the filmpositioning.
 15. Flow regulator according to claim 1, wherein themembrane surface and/or the substrate surface within said cavityincluding said pillars comprise an anti-bonding layer.
 16. Flowregulator according to claim 1, wherein the surfaces in contact with thefluid are coated with hydrophilic and/or anticorrosive agents.
 17. Flowregulator according to claim 1, comprising an actuator adapted to exertpressure on said membrane.
 18. Flow regulator according to claim 1,wherein said membrane comprises strain gauges.
 19. Flow regulatoraccording to claim 1, comprising a filter.